Stimulants

Stimulants are substances that induce a number of characteristic symptoms. CNS effects include alertness with increased vigilance, a sense of well-being, and euphoria. Many users experience insomnia and anorexia, and some may develop psychotic symptoms. Stimulants have peripheral cardiovascular activity, including increased blood pressure and heart rate. ^[1] They encompass a broad category of substances, including those prescribed for medical conditions; those manufactured for illicit substance abuse; and those found in over-the-counter (OTC) decongestants, herbal extracts, caffeinated beverages, and cigarettes.

A number of stimulants are classified by the US Drug Enforcement Agency (DEA) as controlled substances. The initial section of this article reviews the different stimulants classified by the DEA. Several of these stimulants have not been significantly prescribed, abused, or investigated in the United States; consequently, limited data are available. Stimulants that have been studied and classified by the DEA, several OTC drugs, and herbal medications with active stimulant ingredients are discussed. The mechanism of action of these stimulants, when known, is mentioned. Typical signs and symptoms of stimulant toxicity, along with appropriate pharmacologic and nonpharmacologic treatment, are also reviewed.

Caffeine, cocaine, amphetamines, nicotine, and the therapeutic use of stimulants for treatment-resistant depression and attention deficit (hyperactivity) disorder are not discussed in this article. See Cocaine-Related Psychiatric Disorders, Amphetamine-Related Psychiatric Disorders, Caffeine-Related Psychiatric Disorders, Nicotine Addiction, and ADHD for further information on these topics.

For excellent patient education resources, see eMedicineHealth's patient education articles Club Drugs, Cocaine Abuse, Drug Dependence and Abuse, Narcotic Abuse, and Substance Abuse.

The following is the DEA classification of controlled substances. This is not an exclusive list. For a comprehensive list see the Controlled Substance Schedule from the DEA: ^[2]

Schedule I

These substances have no accepted medical use in the United States and have a high abuse potential. They cannot be prescribed.

Schedule I stimulants include the following:

• Aminoxaphen - Aminorex

• Cathinone

• Fenethylline

• Methcathinone

• Mephedrone

• Methylaminorex

• Amphetamine variants (eg, 3,4-methylenedioxymethamphetamine [MDMA], N -ethylamphetamine, N,N -dimethylamphetamine)

Schedule II

These substances have a high abuse potential with severe psychic or physical dependence liability. Schedule II controlled substances consist of certain narcotic, stimulant, and depressant drugs. Prescriptions must be written in ink or typewritten and must be signed by the practitioner except in a genuine emergency, in which case the practitioner is required to supply written confirmation of the verbal order within 72 hours. No renewals may be prescribed.

Schedule II stimulants include the following:

• Cocaine

• Dextroamphetamine and amphetamine - Adderall

• Dextroamphetamine - Dexedrine

• Lisdexamfetamine dimesylate - Vyvanse ^[3]

• Methamphetamine - Desoxyn

• Methylphenidate - Concerta, Daytrana, Focalin, Methylin, Metadate-ER, Ritalin

• Phenmetrazine - Preludin

• Biphetamine

Schedule III

These substances have an abuse potential less than those in schedules I and II, including compounds containing limited quantities of certain narcotic and nonnarcotic drugs. Prescriptions may be oral or written, and up to 5 renewals are permitted within 6 months.

Schedule III stimulants include the following:

• Benzphetamine - Didrex

• Chlorphentermine

• Clortermine

• Phendimetrazine tartrate - Plegine, Prelu 2

Schedule IV

These substances have an abuse potential less than those in schedule III. Prescriptions may be oral or written, and up to 5 renewals are permitted within 6 months.

Schedule IV stimulants include the following:

• Armodafinil - Nuvigil

• Diethylpropion hydrochloride - Tenuate

• Fencamfamin

• Fenproporex

• Mazindol - Sanorex, Mazanor

• Mefenorex

• Modafinil - Provigil

• Norpseudoephedrine

• Pemoline - Cylert (No longer available in United States)

• Phentermine - Fastin, Ionamin, Adipex

• Pipradrol

• Sibutramine - Meridia (withdrawn from US market October 8, 2010)

Schedule V

These substances have an abuse potential less than those in schedule IV. Schedule V controlled substances consist of preparations containing limited quantities of certain narcotic drugs and are generally for antitussive and antidiarrheal purposes. These drugs are subject to state and local regulation, and a prescription may not be required. Schedule V stimulants include pyrovalerone.

Schedule I drugs

The stimulants listed on schedule I are more potent than cocaine and have no established medical use. Based on animal studies, aminorex, methyl-aminorex, methcathinone, and cathinone are more potent relative to cocaine.

Aminorex is a stimulant synthesized in the early 1960s. It diminishes appetite and stimulates motor activity in animals. Aminorex and methyl-aminorex increase available catecholamines at the neural synapse, thereby acting as indirect sympathomimetic agents. Aminorex was removed from the market 30 years ago because of reports of chronic pulmonary hypertension.

Methyl-aminorex is a derivative of aminorex and has also been abused. The street term "ice" is usually indicative of methamphetamine. However, in Philadelphia and Florida, 4-methyl-aminorex has been identified in the street drug sold as ice.

Methcathinone, isolated in 1957, was initially produced for use as an appetite suppressant. It is structurally related to amphetamine and cathinone, a stimulant found in nature. Methcathinone was not marketed because of the recognized addictive potential, but it emerged as a common drug of abuse in the former Soviet Union during the 1970s. It was illegally synthesized by oxidation of ephedrine and first appeared in the United States in rural Michigan in 1989. Methcathinone was made a schedule I drug in 1992, and its use has not spread widely in the United States beyond the northern Midwest region.

Mephedrone (4-methyl-methcathinone) was a legally available congener of methcathinone; however, it has been increasingly used/abused in the United States, Australia, and Europe and was placed on schedule I by the DEA in 2011. A survey of 100 users in England indicated that the drug has characteristics similar to cocaine, with a short duration of action and a high potential for abuse and dependence. ^{[4, 5]}

A web-based survey of 1,006 individuals who admitted mephedrone use, which is the largest survey to-date, found that users consider its effects to compare best with those of MDMA; the availability, low price, and reliable purity were reported to be appealing. ^[6]

Cathinone is the active chemical in a shrub commonly known as khat (Catha edulis) and has been abused for centuries.

MDMA (3,4-Methylenedioxymethamphetamine), which is commonly known as ecstasy, "E," or "X," is derived from methamphetamine and the addition of another methyl group. This additional methyl group increased the compound lipophilicity, leading to its rapid entry into the brain.

MDMA acts as an indirect sympathomimetic, stimulating release and inhibiting reuptake of epinephrine, norepinephrine, and dopamine. Although structurally similar to amphetamines, it is psychoactively complex. Unlike amphetamines, it directly stimulates 5HT2 1A autoreceptors. It also stimulates the release of serotonin and inhibits its reuptake.

MDMA also directly affects other neurotransmitters including histamine, GABA, acetylcholine, and dopamine receptors, and binds to the norepinephrine transporter protein. In addition, it has several pharmacokinetic effects that add to its effects. MDMA inhibits the tryptophan hydroxylase (the rate-limiting step of serotonin synthesis) along with MAO A and B activity and inactivates the cytochrome P450 2D6 enzyme for several days after MDMA ingestion, further increasing the drug toxicity. MDMA rapidly induces tolerance and diminishing responsiveness via a unique mechanism (ie, destruction of serotonergic axon terminals).

Synthesized in 1910, MDMA was patented 2 years later by Merck. Initial plans for the drug were to market it as an appetite suppressant. Although soldiers used it during World War I, the drug did not see widespread use until the 1970s. MDMA is the prototypical empathogen and entactogen drug, meaning that it has unique emotional and prosocial effects; for its distinct ability to enhance empathy and communication, MDMA was, in fact, used as an adjunct to psychotherapy in the 1970s and 1980s. Illicit use under the street name ecstasy was initially limited to all-night dance parties (ie, raves). Because of concerns regarding addiction and potential toxicity, MDMA was labeled as a schedule I hallucinogen in 1985.

The use of MDMA has been increasing in prevalence. A study of 50,000 high school students found that the prevalence in high school seniors increased from 6% to 11% between 1996 and 2000. A study by Strote et al of more than 14,000 US college students estimated that the prevalence of MDMA use increased from 2.8% to 4.7% between 1997 and 1999. ^[7]

More recently, data collected during 2005-2009 estimate that in certain communities (ie, Los Angeles County [LAC]) the prevalence of use has increased from 5.2 to 13.4 per 100,000 LAC residents. During the same period, according to the LAC Reporting System of drug abuse treatment statistics, the number of LAC residents citing MDMA as their drug of choice increased by 650%, from 0.22 to 1.65 per 100,000 LAC residents. ^[8]

Similar to other stimulants, MDMA may cause tachycardia, elevated blood pressure, mydriasis, increased energy, anorexia, and increased concentration. ^[9] Doses of MDMA are typically in the range of 50-250 mg. Although MDMA may cause alterations in color perception, patients do not usually develop frank hallucinations. Undesirable adverse effects may include nausea, diaphoresis, anorexia, tremor, myoclonus, tics, paresthesias, nystagmus, hyperreflexia, hypertension, urinary retention, and ataxia.

Regular users often need to increase their doses, and heavy users may snort or inject MDMA to obtain desired effects.

Schedule II drugs

See Cocaine-Related Psychiatric Disorders and Amphetamine-Related Psychiatric Disorders for a detailed discussion of those schedule II stimulants.

Amphetamines include dextroamphetamine and methamphetamine. Amphetamines act as stimulants by releasing presynaptic dopamine, in contrast to cocaine, which inhibits reuptake of dopamine.

Amphetamines were initially used in inhalers for nasal congestion in the 1930s. The use of amphetamines, which were not controlled substances, spread to athletes, truck drivers, and the general population to promote alertness. ^[10] Amphetamines are currently used to treat narcolepsy and attention deficit hyperactivity disorder (ADHD). They have been used and abused for weight control in individuals with eating disorders or obesity.

Methylphenidate is a piperidine that acts in a similar pharmacologic manner but is not structurally an amphetamine. It also has more prominent CNS versus peripheral stimulant activity.

Methamphetamine can be created from ephedrine by drug dealers in home laboratories. Methamphetamine effects are more pronounced in the CNS, with relatively diminished peripheral activity.

Dextroamphetamine was used by soldiers to increase alertness and stamina during World War II. It has more prominent CNS activity relative to peripheral stimulant activity.

Phenmetrazine is a stimulant that was widely prescribed for treatment of obesity in the United States in the 1950s and 1960s and in several European countries such as Sweden and Germany. It became an extremely popular drug of abuse. A study of drug use among criminals found that for many methamphetamine addicts, phenmetrazine became their drug of choice. In 1971, phenmetrazine was placed into the schedule II category. Abuse of this drug has ended because phenmetrazine was never illicitly manufactured and is no longer prescribed.

Newer classes of stimulants have similar properties to amphetamines; however, they are less likely to lead to dependence and abuse.

The appetite-suppressant effect of stimulants has been apparent for many decades. In more recent years, stimulant medications with a lower risk of abuse (often related to decreased potency of the agents) have been developed for the treatment of obesity. Because of this lower risk, the newer anorectic agents were placed in schedule III and schedule IV. These drugs include dexfenfluramine, phentermine, fenfluramine, mazindol, diethylpropion, and fenproporex. Phentermine, mazindol, and diethylpropion affect noradrenergic systems, whereas fenfluramine modulates serotonergic activity. The efficacy of these agents in weight reduction is limited in part due to tolerance that develops with long-term treatment.

Schedule III drugs

A number of stimulants listed by the DEA are not widely used or abused. Limited information is available for the class III stimulants. Clortermine, a class III agent, has been available for many years and has been found in several trials to be more effective than placebo in obesity treatment. It has not been used to any significant degree.

Schedule IV drugs

Diethylpropion has been available since 1960. Several studies have proven diethylpropion to be efficacious for the short-term treatment of obesity. It reportedly has a low abuse potential. The mechanism of action of diethylpropion is similar to that of dextroamphetamine, although at a tenth of the potency.

At the usual prescribed dose of 25-75 mg, it increases blood pressure and body temperature and reduces energy intake and sleep.

In animal studies, diethylpropion was able to serve as a substitute for cocaine in food-deprived rats.

Initial open-labeled studies of patients with cocaine dependency suggested that diethylpropion might be an effective treatment to maintain abstinence. These findings were not confirmed by a placebo-controlled double-blind study.

Fenproporex, although initially marketed as a nonstimulant anorectic agent, is metabolized to several active amphetamines.

Phentermine and fenfluramine are the active ingredients of the infamous Phen-Fen anorectic agent, which has been associated with cardiac valvular disease. Fenfluramine has been removed from the market, but phentermine remains available as a treatment for obesity. Various formulations with doses of 15-37.5 mg are available. Cardiac valvular disease does not appear to be a risk with the use of phentermine alone.

Mazindol inhibits norepinephrine reuptake and is structurally related to tricyclic antidepressants. Mazindol reduces appetite with fewer stimulant properties and less potential for abuse than amphetamine. Mazindol appeared effective in the treatment of obesity in open-labeled studies; however, patients have developed atrial fibrillation and syncope, thus discouraging widespread use of this medication.

Modafinil is an atypical stimulant that has lower abuse potential than most other stimulants.

Modafinil affects the hypocretin/orexin neuropeptide in the hypothalamus. This chemical has a role in the stimulation of appetite and in alertness in the canine version of narcolepsy. Modafinil is currently indicated for the treatment of human narcolepsy. It does not act on noradrenergic, serotonergic, or dopaminergic systems.

While both amphetamines and modafinil increase wakefulness, only amphetamines increase activity in regions of the brain such as the basal ganglia and nucleus accumbens. Considered a CNS reward center, the nucleus accumbens has been associated with positive reinforcement and implicated in cocaine abuse.

One study by Jasinski compared modafinil to methylphenidate and found significant differences between the two. ^[11] Doses were 200-800 mg for modafinil and 45-90 mg for methylphenidate. The Amphetamine Scale, which is used to identify stimulants by their subjective effects, was used to identify amphetaminelike qualities of these drugs. Modafinil did not produce elevations in the Amphetamine Scale, suggesting that the subjective effects of this drug are qualitatively different from traditional stimulants.

Certain chemical properties of modafinil reduce its potential for abuse. Modafinil is insoluble in water and thus cannot be readily injected. Also, it degrades with heating, preventing a pharmacologic effect if smoked. Modafinil has a long half-life, which would further minimize its abuse potential.

In fact, Dackis et al investigated modafinil as a potential treatment for cocaine dependence. ^[12] His group conducted a double-blind, placebo-controlled 8-week trial with 62 patients dependent on cocaine. They found that modafinil improved cocaine abstinence.

Armodafinil is the R-enantiomer of modafinil. The R-enantiomer has a longer half life (10-14 h) than the S-enantiomer (3-4 h). A study comparing the 2 drugs at doses of 200 mg found that modafinil had an earlier peak plasma concentration and armodafinil had higher plasma concentrations at 6-14 hours. These characteristics of armodafinil have been suggested to offer the advantage of once daily dosing and longer duration of wakefulness than modafinil. Armodafinil has been studied in the treatment of sleep disorders, including obstructive sleep apnea and narcolepsy.

Pemoline is a stimulant with similar pharmacologic activity to methylphenidate that has been used to treat ADHD. It has a potential for serious hepatotoxicity; therefore, stimulants with safer adverse effect profiles may be preferable clinically. The United States Food and Drug Administration (FDA) concluded that the overall risk of liver toxicity from pemoline outweighs the benefits. In May 2005, Abbott chose to stop sales and marketing of their brand of pemoline (Cylert) in the United States. In October 2005, all companies that produced generic versions of pemoline also agreed to stop sales and marketing of pemoline.

Sibutramine (Meridia) is a combination serotonin and norepinephrine and dopamine reuptake inhibitor whose appetite-suppressive effects appear to be related to its noradrenergic action. When its noradrenergic activity is blocked, the appetite suppression is lost. Selective serotonin reuptake inhibitors cause initial transient anorexia without causing long-term weight loss. Sibutramine is no longer marketed.

On October 8, 2010, Abbott and the US Food and Drug Administration (FDA) announced that sibutramine (Meridia) is being withdrawn from the market because of increased risk of myocardial infarction (MI) and stroke. Europe suspended sibutramine from the market earlier this year.

The FDA requested the market withdrawal after reviewing data from the Sibutramine Cardiovascular Outcomes Trial (SCOUT). SCOUT was initiated as part of a postmarket requirement to look at cardiovascular safety of sibutramine after the European approval of this drug. The trial demonstrated a 16% increase in the risk of serious heart events, including nonfatal MI, nonfatal stroke, the need to be resuscitated once the heart stopped, and death, in a group of patients given sibutramine and another given placebo. A very small difference (2.5%) in weight loss was noted between the placebo group and the group that received sibutramine. ^[13]

Remaining available weight loss products in the US include orlistat (Alli, Xenical), phentermine (Adipex-P), and diethylpropion.

Schedule V stimulants

Pyrovalerone is the only class V stimulant listed by the DEA. This drug is used in Europe, but no information is available in English-language medical journals.

Other stimulants

Phenylpropanolamine (PPA) is closely related to ephedrine and has been recognized as having anorectic properties without significant risk of dependence.

In fact, a controlled study of healthy volunteers found PPA to be mildly aversive, with a greater proportion of patients preferring placebo to 75 mg of PPA. In the same study, dextroamphetamine was confirmed as having strong reinforcing behaviors.

A number of case reports suggest an association between intracranial hemorrhage and the use of PPA. A study designed to investigate this risk found that the use of PPA in appetite suppressants was an independent risk factor for hemorrhagic strokes in women. As a result, the US Food and Drug Administration (FDA) issued a warning, and PPA was removed from the market in October 2000.

Ephedrine, norephedrine, and pseudoephedrine can be found in numerous OTC medications. For many years, ephedrine has been used in numerous OTC drugs as a nasal decongestant and appetite suppressant.

Alternative medicines, including herbal supplements, have gained widespread popularity and are currently a multibillion-dollar business. Hundreds of these supplements contain stimulants as active ingredients.

In 1994, the Dietary Supplement Health and Education Act essentially exempted dietary supplements from FDA regulation. This allows stimulants to be sold as food supplements, thereby avoiding governmental regulation. Although these drugs have no proven efficacy in the treatment of any medical conditions, they are marketed as solutions to common problems such as low energy and obesity.

Without regulation, the actual content of active agents is often unreliable. In several cases, significant quantities of schedule IV controlled substances, such as norpseudoephedrine, were isolated from these products. The herb ma-huang, which consists of the dried stems of the Ephedra equisetina plant, contains ephedrine, norephedrine, pseudoephedrine, and norpseudoephedrine. It has been used for centuries in China.

Ephedrine was first isolated in 1885 and, shortly after, was used to treat asthma. Many OTC medications contain ephedrine and pseudoephedrine for treating asthma and allergic rhinitis. Herbs with ephedrine are sold as food and exercise supplements. Previously used by physicians as treatments for asthma, hypotension, and depression, these medications have been replaced by safer, more selective agents.

Ephedrine is also structurally related to amphetamines and acts as a sympathomimetic that has nonspecific alpha- and beta-adrenergic agonist activity. Ephedrine acts as a direct sympathomimetic agent and also acts via increasing catecholamine levels in the brain and cardiovascular system.

Ephedrine has a half-life of 5 hours and is excreted primarily unchanged in the urine. Common effects include bronchodilation, tachycardia, vasoconstriction, transient hypertension, nervousness, insomnia, appetite suppression, and headache.

These drugs are not safe and may cause serious toxicity. Long-term use at doses recommended by some manufacturers has been found to be a cause of fatal cardiomyopathy in an otherwise healthy 23-year-old man. ^[14]

Additionally, use of ephedrine-containing compounds appears to be a potential cause of nephrolithiasis. A study by Powell et al found an association between ephedrine usage and kidney stone formation. ^[15] However, the most serious complications arise from its adverse cardiovascular and neurologic effects. It has been linked to 34 deaths and 800 cited serious complications, including hypertension, arrhythmias, cardiomyopathy, myocardial infarction, hemorrhagic stroke, seizures, nephrolithiasis, and psychosis.

These products often contain both ephedrine and caffeine. The combination of these agents can be synergistic, increasing blood pressure and the risk of stroke. Owing to public health risks, the FDA initially proposed placing limitations on the use of these drugs.

In February 2004, the FDA prohibited the sale of dietary supplements containing ephedrine citing that they constitute an unreasonable risk due to their potential health risks and questionable health benefits. Most ephedra-containing dietary supplements have been removed from the market.

History

A thorough history of recent and past use of illicit drugs, herbal medications, food supplements, caffeine, alcohol, and prescribed medications is critical. Elevated mood, increased alertness, increased energy, insomnia, and anorexia are all common symptoms associated with stimulant use. Chest pain, tachypnea, nausea, abdominal pain, and headaches may also be associated with such use. Long-term stimulant use may result in tolerance, weight loss, and potential adverse psychiatric symptoms such as irritability, aggression, impulsivity, hallucinations, and delusions.

Use of MDMA is distinguished from stimulant intoxication by the propensity for calmness and empathy. Common adverse effects may include restlessness, anxiety, trismus, fever, and impaired memory.

Physical

Increases in blood pressure, heart rate, and pupillary dilation are common. Stimulant use may result in hyperthermia, hyponatremia, arrhythmias, myocardial infarction, and hemorrhagic stroke. Due to the excessive dopaminergic discharge, dyskinesias may be present.

MDMA short-term effects include dehydration, hyperthermia, and heat stroke. Overdoses can simulate methamphetamine overdose. Rhabdomyolysis and acute renal failure have also been reported.

Mental status examination (during stimulant intoxication) is significant for the following:

• Attitude - Tense, anxious, restless, agitated

• Psychomotor activity - Increased; dyskinesias may be present

• Mood/affect - Good/euphoric or irritable and labile

• Speech - Talkative

• Thought processes - Flight of ideas; tangentiality

• Thought content - Paranoia; auditory, visual, and tactile (formication) hallucinations; grandiosity; hypersexuality; homicidal ideation

• Insight or judgment - Impaired

• Orientation - Confusion, delirium

• Memory - Although small doses of stimulants may improve alertness and task performance, the heavy use associated with stimulant abuse can be detrimental to memory and result in coma.

Mental status examination (during stimulant withdrawal) is significant for the following:

• Behavior - Sedated

• Psychomotor activity - Decreased

• Mood or affect - Depressed or irritable

• Speech - Decreased production

• Thought processes or content - Linear, at times with suicidal ideation and drug craving. Homicidal ideation; paranoia

• Insight or judgment - Variable

• Orientation - May be normal or close to normal

• Cognition - Poor attention and concentration

• Memory - Likely impaired due to sleep deprivation, associated fatigue, decreased attention and irritability

Mortality and morbidity

Adverse effects of the more common stimulants are discussed in other articles on cocaine and methamphetamine abuse. See Cocaine-Related Psychiatric Disorders and Amphetamine-Related Psychiatric Disorders for a detailed discussion.

Toxicity related to MDMA use differs from other stimulants. In animals, single high-dose or multiple lower doses cause loss of 5-HT axon terminals. Similar findings have been noted in humans who abuse MDMA. Clinically, memory deficits along with mood and anxiety symptoms are strongly correlated to cumulative use of MDMA.

Tolerance develops with MDMA due to a gradual destruction of serotonergic neuronal axon terminals.

A review of the literature in 2003 by Patel et al noted 86 fatalities associated with MDMA use. ^[16]

In 1999, McElhatton et al noted an increased incidence of congenital anomalies associated with MDMA abuse, including musculoskeletal and cardiac abnormalities. ^[17]

Other conditions and diagnoses to consider include the following:

• Delirium (toxic-metabolic, infectious)

• Hyperthyroidism

• Acute intermittent porphyria

• Lysergic acid diethylamide (LSD) intoxication

• Phencyclidine (PCP) intoxication

• Caffeine overuse

• Neuroleptic malignant syndrome

• Alcohol, benzodiazepine, or barbiturate withdrawal

• Anticholinergic overdose

• Schizophrenia

• Bipolar disorders

• Anxiety disorders

Drug screens for amphetamines lack specificity for MDMA. If testing is not performed within several hours of cocaine use, findings are often negative for the parent compound. However, cocaine metabolites can be identified for several days after ingestion. Urine drug screens may be useful for excluding other substances (eg, PCP, cannabis) that may mimic stimulant intoxication.

Routine evaluations should include an ECG and electrolyte evaluation. Users of MDMA have a risk of dehydration. Cases of hyponatremia due to excessive hypotonic fluid intake have been reported with MDMA abuse. Any patient with an altered mental status should receive consideration for immediate cranial neuroimaging with a CT scan to help exclude acute intracranial pathology.

A specific antidote does not exist for acute stimulant intoxication. Activated charcoal should be prescribed in a case of acute overdose. Otherwise the treatment should target specific signs and symptoms such as hypertension, agitation, seizures, and hyperthermia. In the study of fatalities related to MDMA ingestion by Patel et al, a significant delay occurred between onset of symptoms and health care treatment in the cases reviewed. ^[16] Rapid supportive treatment may reduce mortality.

Supportive therapy

Supportive therapy involves some or all of the following:

• Acute intoxication usually presents with increased sensitivity to sensorial stimuli and paranoia. As such, decreasing the patient's level of stimulation (keep voice low, dim lights, minimize touch) and working with the patient's paranoid state (reduce eye contact, respect personal space, do not approach from behind) is important. ^[18]

• Establish and maintain ABCs.

• Decontamination with gastric lavage may be appropriate in cases of recent ingestion.

• Monitor vital signs and hydrate with intravenous fluids.

• Withdrawal related insomnia may be treated with trazodone (75-200 mg), hydroxyzine (25-50 mg), or diphenhydramine (50-100 mg) at bedtime.

• Benzodiazepines should be avoided unless the patient is also in detox from alcohol/benzodiazepines/opiates.

• Neuroleptics may be used for the symptomatic treatment of psychosis.

• Physical restraints may be required in certain cases.

• The intensity and duration of withdrawal symptoms varies depending on the type of stimulant, dose, duration of use, as well as underlying psychiatric pathology.

• Common withdrawal symptoms may include dysphoria, anxiety, and irritability, decreased energy (manifested as reported fatigue, psychomotor retardation and hypersomnia), hyperphagia, decreased concentration, and paranoia. The withdrawal symptoms are uncomfortable but not life threatening; consequently, no current recommendations for a stimulant-detoxification regimen are available.

• Stimulant withdrawal dysphoria is common and does not in itself represent an indication for an antidepressant. However, a thorough assessment (including consideration of an antidepressant) is recommended for persistent (longer than a week) depressive symptoms at a level of moderate or severe or associated with suicidal ideation/attempts.

Stimulant dependence

Studies have investigated the use of newer stimulants with lesser potential for abuse as transitional replacements to cocaine. Over time, cravings for stimulants such as cocaine appear to dissipate regardless of placebo administration or alternative stimulant treatment. The relatively small, double-blind, placebo-controlled study by Dackis et al suggested that modafinil may have use in the treatment of cocaine dependence. ^[12]

Outpatient and inpatient nonpharmacologic treatment of stimulant dependence has been shown to be beneficial. However, relapse after treatment is common. Educating patients and their families about substance dependence and abuse is important. See Patient and Family Education.

Consultation with a psychiatrist may be indicated for patients with a history of mental illness, current psychosis, evidence of self-harm, or violent behavior. Brief psychiatric observation and treatment of acute agitation with referral to a treatment program may suffice for some patients. However, persistent paranoia, homicidal ideation, or severe dysphoria with suicidal ideation during stimulant withdrawal may necessitate psychiatric hospitalization. Comorbid psychiatric disorders, including depression, psychotic disorders, and personality disorders (eg, antisocial and borderline personalities), should be identified, and appropriate treatment should be initiated.

Educating patients and their families about substance dependence and abuse is important. Potential medical complications of stimulant abuse should be discussed with patients. Those who abuse stimulants need to identify triggers for relapse, often with the assistance of substance abuse counselors. Recognizing behaviors of family members that allow substance abuse to occur can help patients achieve abstinence. See Cocaine-Related Psychiatric Disorders for further information.

Patients can find online information on stimulant abuse and support groups at the following Web sites.

• National Institute on Drug Abuse

• Division of Alcohol and Drug Abuse

• The Anti-Meth Site

• Help for Drug Problems

• Narcotics Anonymous